The study proposed will identify genes involved in predisposing to non- insulin dependent diabetes mellitus (NIDDM). The target population is Hispanic, a minority group known to have a higher prevalence of diabetes (10-15 %) than in most Caucasians (2-4%). We will use two approaches to detecting linkage between the NIDDM phenotype and a number of candidate marker loci. In combination, these two methods promise a high probability of success under a number of possible hypothesized models for the NIDDM phenotype. First, we will ascertain 200 affected-sib-pairs and use the sib-pair identity-by-descent method of analysis. The main strength of this method is that it is non-parametric, that is, no model for the mode of inheritance of the NIDDM phenotype is required, thus avoiding problems of delayed age-of-onset and lack of penetrance. Furthermore, the sib-pair analysis has the potential to identify multiple loci that may determine the NIDDM phenotype. Second, we will ascertain 25 large (20-25 member), multiplex families and use classical linkage analysis to detect linkage separately within each family. The main strength of this method is that by restriction to a single family at a time for analysis, we should avoid heterogeneity in the NIDDM phenotype, if such heterogeneity exists. We will use epidemiological and clinical data on, for example, age-at-onset, presence of hyperinsulinemia or insulin resistance in the families of our probands to classify subsets of NIDDM which can be formally tested for heterogeneity. We will examine a large number of genes which can be considered candidate genes for NIDDM because of their biochemical role in glucose homeostasis and genes which have been previously reported to be associated with NIDDM. More important to the proposed study is the fact that for each of the candidate genes, we will use as markers short tandem repeat, microsatellite, polymorphisms which are highly informative, average heterozygosity equal to or less than 0.7, and are easily typed by DNA amplification using the polymerase chain reaction (PCR) to maximize the amount of genetic information extracted from our sample of relatives. We will take advantage of a long-term study of the Hispanic population of the San Luis Valley of Southern Colorado in which the epidemiologic characteristics of NIDDM have been well documented, and where the elevated prevalence of NIDDM has allowed us to identify a large cohort of affected sib-pairs and large, multigenerational families.